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Malignant and Non-malignant Atypical Circulating Cell in Cancer: Their Heterogeneity and Plasticity

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A topical collection in Cancers (ISSN 2072-6694). This collection belongs to the section "Cancer Metastasis".

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Dr. Emilie Mamessier-Birnbaum

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Predictive Oncology Laboratory, Cancer Research Center of Marseille (CRCM), Inserm U1068,CNRS UMR7258, Institut Paoli-Calmettes, Aix Marseille Université, 13009 Marseille, France
Interests: cancer metastasis; circulating tumor cells; microenvironment; cancer heterogeneity and plasticity; biomarkers; resistance to treatment

Dr. Claire Acquaviva

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Guest Editor

Predictive Oncology Laboratory, Cancer Research Center of Marseille (CRCM), Inserm U1068,CNRS UMR7258, Institut Paoli-Calmettes, Aix Marseille Université, 13009 Marseille, France
Interests: Circulating Tumor Cells; Tumor Plasticity; Tumor Cell Cultures

Topical Collection Information

Dear Colleagues,

Solid tumors induce the presence of atypical cell types in the blood circulation. The ease of sampling these atypical circulating cells, although counterbalanced by their scarceness, holds the potential to help us better understand tumor evolution and drug resistance.

The most-described atypical circulating cells in cancers are called circulating tumor cells (CTCs). They can potentially generate distant metastasis, and many studies demonstrate their role in predicting clinical outcomes. The initial view that CTCs are defined by their epithelial phenotype has been challenged by the discovery that CTCs are a heterogeneous cell population characterized by plasticity and can also include cells that have lost some of their epithelial traits. Moreover, reports indicate that many other atypical circulating cells can be found in the blood of cancer patients, and, despite not being of epithelial origin and malignant, can play an important role in metastasis and hold strong prognostic value.

This Special Issue will focus on atypical circulating cells—of a malignant origin or not—found in the blood of cancer patients, and how their heterogeneity can provide us with a better understanding of tumor behavior. The aim of this Special Issue is to provide insights into the physical, biological, and chemical cues that generate this heterogeneity and trigger cell plasticity/reprogramming, such as adjustment to stressful conditions or changes favoring tumor progression.

We look forward to your contribution to this Special Issue.

Dr. Emilie Mamessier-Birnbaum
Dr. Claire Acquaviva
Guest Editors

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Keywords

circulating tumor cells
atypical circulating cells
cellular plasticity
cellular heterogeneity
cell reprogramming
epithelial-to-mesenchymal transition
resistance to treatment
physical cues
stress
anti-tumor immunity
anoikis

Published Papers (9 papers)

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2023

Jump to: 2022, 2021

22 pages, 3232 KiB

Open AccessArticle

Phenotypic Plasticity in Circulating Tumor Cells Is Associated with Poor Response to Therapy in Metastatic Breast Cancer Patients

by Evan N. Cohen, Gitanjali Jayachandran, Hui Gao, Phillip Peabody, Heather B. McBride, Franklin D. Alvarez, Megumi Kai, Juhee Song, Yu Shen, Jie S. Willey, Bora Lim, Vicente Valero, Naoto T. Ueno and James M. Reuben

Cancers 2023, 15(5), 1616; https://doi.org/10.3390/cancers15051616 - 6 Mar 2023

Cited by 6 | Viewed by 3909

Abstract

Circulating tumor cells (CTCs) are indicators of metastatic spread and progression. In a longitudinal, single-center trial of patients with metastatic breast cancer starting a new line of treatment, a microcavity array was used to enrich CTCs from 184 patients at up to 9 timepoints at 3-month intervals. CTCs were analyzed in parallel samples from the same blood draw by imaging and by gene expression profiling to capture CTC phenotypic plasticity. Enumeration of CTCs by image analysis relying primarily on epithelial markers from samples obtained before therapy or at 3-month follow-up identified the patients at the highest risk of progression. CTC counts decreased with therapy, and progressors had higher CTC counts than non-progressors. CTC count was prognostic primarily at the start of therapy in univariate and multivariate analyses but had less prognostic utility at 6 months to 1 year later. In contrast, gene expression, including both epithelial and mesenchymal markers, identified high-risk patients after 6–9 months of treatment, and progressors had a shift towards mesenchymal CTC gene expression on therapy. Cross-sectional analysis showed higher CTC-related gene expression in progressors 6–15 months after baseline. Furthermore, patients with higher CTC counts and CTC gene expression experienced more progression events. Longitudinal time-dependent multivariate analysis indicated that CTC count, triple-negative status, and CTC expression of FGFR1 significantly correlated with inferior progression-free survival while CTC count and triple-negative status correlated with inferior overall survival. This highlights the utility of protein-agnostic CTC enrichment and multimodality analysis to capture the heterogeneity of CTCs. Full article

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2022

Jump to: 2023, 2021

16 pages, 2074 KiB

Open AccessArticle

Dissecting Molecular Heterogeneity of Circulating Tumor Cells (CTCs) from Metastatic Breast Cancer Patients through Copy Number Aberration (CNA) and Single Nucleotide Variant (SNV) Single Cell Analysis

by Tania Rossi, Davide Angeli, Michela Tebaldi, Pietro Fici, Elisabetta Rossi, Andrea Rocca, Michela Palleschi, Roberta Maltoni, Giovanni Martinelli, Francesco Fabbri and Giulia Gallerani

Cancers 2022, 14(16), 3925; https://doi.org/10.3390/cancers14163925 - 14 Aug 2022

Cited by 10 | Viewed by 3198

Abstract

Circulating tumor cells’ (CTCs) heterogeneity contributes to counteract their introduction in clinical practice. Through single-cell sequencing we aim at exploring CTC heterogeneity in metastatic breast cancer (MBC) patients. Single CTCs were isolated using DEPArray NxT. After whole genome amplification, libraries were prepared for copy number aberration (CNA) and single nucleotide variant (SNV) analysis and sequenced using Ion GeneStudio S5 and Illumina MiSeq, respectively. CTCs demonstrate distinctive mutational signatures but retain molecular traces of their common origin. CNA profiling identifies frequent aberrations involving critical genes in pathogenesis: gains of 1q (CCND1) and 11q (WNT3A), loss of 22q (CHEK2). The longitudinal single-CTC analysis allows tracking of clonal selection and the emergence of resistance-associated aberrations, such as gain of a region in 12q (CDK4). A group composed of CTCs from different patients sharing common traits emerges. Further analyses identify losses of 15q and enrichment of terms associated with pseudopodium formation as frequent and exclusive events. CTCs from MBC patients are heterogeneous, especially concerning their mutational status. The single-cell analysis allows the identification of aberrations associated with resistance, and is a candidate tool to better address treatment strategy. The translational significance of the group populated by similar CTCs should be elucidated. Full article

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16 pages, 715 KiB

Open AccessReview

Circulating Cells with Macrophage-like Characteristics in Cancer: The Importance of Circulating Neoplastic-Immune Hybrid Cells in Cancer

by Thomas L. Sutton, Ranish K. Patel, Ashley N. Anderson, Stephen G. Bowden, Riley Whalen, Nicole R. Giske and Melissa H. Wong

Cancers 2022, 14(16), 3871; https://doi.org/10.3390/cancers14163871 - 11 Aug 2022

Cited by 31 | Viewed by 5388

Abstract

Cancer remains a significant cause of mortality in developed countries, due in part to difficulties in early detection, understanding disease biology, and assessing treatment response. If effectively harnessed, circulating biomarkers promise to fulfill these needs through non-invasive “liquid” biopsy. While tumors disseminate genetic material and cellular debris into circulation, identifying clinically relevant information from these analytes has proven difficult. In contrast, cell-based circulating biomarkers have multiple advantages, including a source for tumor DNA and protein, and as a cellular reflection of the evolving tumor. While circulating tumor cells (CTCs) have dominated the circulating cell biomarker field, their clinical utility beyond that of prognostication has remained elusive, due to their rarity. Recently, two novel populations of circulating tumor-immune hybrid cells in cancer have been characterized: cancer-associated macrophage-like cells (CAMLs) and circulating hybrid cells (CHCs). CAMLs are macrophage-like cells containing phagocytosed tumor material, while CHCs can result from cell fusion between cancer and immune cells and play a role in the metastatic cascade. Both are detected in higher numbers than CTCs in peripheral blood and demonstrate utility in prognostication and assessing treatment response. Additionally, both cell populations are heterogeneous in their genetic, transcriptomic, and proteomic signatures, and thus have the potential to inform on heterogeneity within tumors. Herein, we review the advances in this exciting field. Full article

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18 pages, 1836 KiB

Open AccessArticle

Identification of Atypical Circulating Tumor Cells with Prognostic Value in Metastatic Breast Cancer Patients

by Alexia Lopresti, Claire Acquaviva, Laurys Boudin, Pascal Finetti, Séverine Garnier, Anaïs Aulas, Maria Lucia Liberatoscioli, Olivier Cabaud, Arnaud Guille, Alexandre de Nonneville, Quentin Da Costa, Emilie Denicolai, Jihane Pakradouni, Anthony Goncalves, Daniel Birnbaum, François Bertucci and Emilie Mamessier

Cancers 2022, 14(4), 932; https://doi.org/10.3390/cancers14040932 - 13 Feb 2022

Cited by 6 | Viewed by 3409

Abstract

Circulating tumor cells have a strong potential as a quasi-non-invasive tool for setting up a precision medicine strategy for cancer patients. Using a second-generation “filtration-based” technology to isolate CTCs, the Screencell™ technology (Sarcelles, France), we performed a large and simultaneous analysis of all atypical circulating tumor cells (aCTCs) isolated from the blood of metastatic breast cancer (mBC) patients. We correlated their presence with clinicopathological and survival data. We included 91 mBC patients from the PERMED-01 study. The median number of aCTCs was 8.3 per mL of blood. Three subsets of aCTCs, absent from controls, were observed in patients: single (s-aCTCs), circulating tumor micro-emboli (CTM), and giant-aCTCs (g-aCTCs). The presence of g-aCTCs was associated with shorter progression free survival and overall survival. This study highlights the heterogeneity of aCTCs in mBC patients both at the cytomorphological and molecular levels. In addition, it suggests the usefulness of the g-aCTC subset as a prognostic factor and a potential stratification tool to treat late-stage mBC patients and improve their chances of benefiting from early clinical trials. Full article

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2021

Jump to: 2023, 2022

16 pages, 1914 KiB

Open AccessReview

Physical Forces and Transient Nuclear Envelope Rupture during Metastasis: The Key for Success?

by Benoit R. Gauthier, Petra I. Lorenzo and Valentine Comaills

Cancers 2022, 14(1), 83; https://doi.org/10.3390/cancers14010083 - 24 Dec 2021

Cited by 8 | Viewed by 4521

Abstract

During metastasis, invading tumor cells and circulating tumor cells (CTC) face multiple mechanical challenges during migration through narrow pores and cell squeezing. However, little is known on the importance and consequences of mechanical stress for tumor progression and success in invading a new organ. Recently, several studies have shown that cell constriction can lead to nuclear envelope rupture (NER) during interphase. This loss of proper nuclear compartmentalization has a profound effect on the genome, being a key driver for the genome evolution needed for tumor progression. More than just being a source of genomic alterations, the transient nuclear envelope collapse can also support metastatic growth by several mechanisms involving the innate immune response cGAS/STING pathway. In this review we will describe the importance of the underestimated role of cellular squeezing in the progression of tumorigenesis. We will describe the complexity and difficulty for tumor cells to reach the metastatic site, detail the genomic aberration diversity due to NER, and highlight the importance of the activation of the innate immune pathway on cell survival. Cellular adaptation and nuclear deformation can be the key to the metastasis success in many unsuspected aspects. Full article

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18 pages, 2971 KiB

Open AccessArticle

CNA Profiling of Single CTCs in Locally Advanced Esophageal Cancer Patients during Therapy Highlights Unexplored Molecular Pathways

by Giulia Gallerani, Tania Rossi, Martina Valgiusti, Davide Angeli, Pietro Fici, Sara De Fanti, Erika Bandini, Claudia Cocchi, Giovanni Luca Frassineti, Massimiliano Bonafè and Francesco Fabbri

Cancers 2021, 13(24), 6369; https://doi.org/10.3390/cancers13246369 - 19 Dec 2021

Cited by 4 | Viewed by 3566

Abstract

Background: Here, we monitored the evolution of CTCs spread in 11 patients affected by locally advanced EC who were undergoing therapy. Methods: In this perspective study, we designed multiple blood biopsies from individual patients: before and after neoadjuvant chemo-radio therapy and after surgery. We developed a multi-target array, named Grab-all assay, to estimate CTCs for their epithelial (EpCAM/E-Cadherin/Cytokeratins) and mesenchymal/stem (N-Cadherin/CD44v6/ABCG2) phenotypes. Identified CTCs were isolated as single cells by DEPArray, subjected to whole genome amplification, and copy number aberration (CNA) profiles were determined. Through bioinformatic analysis, we assessed the genomic imbalance of single CTCs, investigated specific focal copy number changes previously reported in EC and aberrant pathways using enrichment analysis. Results: Longitudinal monitoring allowed the identification of CTCs in at least one time-point per patient. Through single cell CNA analysis, we revealed that CTCs showed significantly dynamic genomic imbalance during treatment. Individual CTCs from relapsed patients displayed a higher degree of genomic imbalance relative to disease-free patients’ groups. Genomic aberrations previously reported in EC occurred mostly in post-neoadjuvant therapy CTCs. In-depth analysis showed that networks enrichment in all time-point CTCs were inherent to innate immune system. Transcription/gene regulation, post-transcriptional and epigenetic modifications were uniquely affected in CTCs of relapsed patients. Conclusions: Our data add clues to the comprehension of the role of CTCs in EC aggressiveness: chromosomal aberrations on genes related to innate immune system behave as relevant to the onset of CTC-status, whilst pathways of transcription/gene regulation, post-transcriptional and epigenetic modifications seem linked to patients’ outcome. Full article

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15 pages, 3238 KiB

Open AccessArticle

Epithelial-to-Mesenchymal Plasticity in Circulating Tumor Cell Lines Sequentially Derived from a Patient with Colorectal Cancer

by Pelin Balcik-Ercin, Laure Cayrefourcq, Rama Soundararajan, Sendurai A. Mani and Catherine Alix-Panabières

Cancers 2021, 13(21), 5408; https://doi.org/10.3390/cancers13215408 - 28 Oct 2021

Cited by 18 | Viewed by 3081

Abstract

Metastasis is a complicated and only partially understood multi-step process of cancer progression. A subset of cancer cells that can leave the primary tumor, intravasate, and circulate to reach distant organs are called circulating tumor cells (CTCs). Multiple lines of evidence suggest that in metastatic cancer cells, epithelial and mesenchymal markers are co-expressed to facilitate the cells’ ability to go back and forth between cellular states. This feature is called epithelial-to-mesenchymal plasticity (EMP). CTCs represent a unique source to understand the EMP features in metastatic cascade biology. Our group previously established and characterized nine serial CTC lines from a patient with metastatic colon cancer. Here, we assessed the expression of markers involved in epithelial–mesenchymal (EMT) and mesenchymal–epithelial (MET) transition in these unique CTC lines, to define their EMP profile. We found that the oncogenes MYC and ezrin were expressed by all CTC lines, but not SIX1, one of their common regulators (also an EMT inducer). Moreover, the MET activator GRHL2 and its putative targets were strongly expressed in all CTC lines, revealing their plasticity in favor of an increased MET state that promotes metastasis formation. Full article

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13 pages, 2524 KiB

Open AccessArticle

CD44v6 Defines a New Population of Circulating Tumor Cells Not Expressing EpCAM

by Guillaume Belthier, Zeinab Homayed, Fanny Grillet, Christophe Duperray, Julie Vendrell, Ilona Krol, Sophie Bravo, Jean-Christophe Boyer, Olivia Villeronce, Jihane Vitre-Boubaker, Diana Heaug-Wane, Françoise Macari-Fine, Jai Smith, Matthieu Merlot, Gérald Lossaint, Thibault Mazard, Fabienne Portales, Jérôme Solassol, Marc Ychou, Nicola Aceto, Emilie Mamessier, François Bertucci, Jean Marc Pascussi, Emmanuelle Samalin, Frédéric Hollande and Julie Pannequin Show full author list Hide full author list

Cancers 2021, 13(19), 4966; https://doi.org/10.3390/cancers13194966 - 2 Oct 2021

Cited by 7 | Viewed by 3797

Abstract

Circulating tumor cells (CTCs) are promising diagnostic and prognostic tools for clinical use. In several cancers, including colorectal and breast, the CTC load has been associated with a therapeutic response as well as progression-free and overall survival. However, counting and isolating CTCs remains sub-optimal because they are currently largely identified by epithelial markers such as EpCAM. New, complementary CTC surface markers are therefore urgently needed. We previously demonstrated that a splice variant of CD44, CD44 variable alternative exon 6 (CD44v6), is highly and specifically expressed by CTC cell lines derived from blood samples in colorectal cancer (CRC) patients. Two different approaches—immune detection coupled with magnetic beads and fluorescence-activated cell sorting—were optimized to purify CTCs from patient blood samples based on high expressions of CD44v6. We revealed the potential of the CD44v6 as a complementary marker to EpCAM to detect and purify CTCs in colorectal cancer blood samples. Furthermore, this marker is not restricted to colorectal cancer since CD44v6 is also expressed on CTCs from breast cancer patients. Overall, these results strongly suggest that CD44v6 could be useful to enumerate and purify CTCs from cancers of different origins, paving the way to more efficacious combined markers that encompass CTC heterogeneity. Full article

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13 pages, 2539 KiB

Open AccessArticle

Is There One Key Step in the Metastatic Cascade?

by Antoine M. Dujon, Jean-Pascal Capp, Joel S. Brown, Pascal Pujol, Robert A. Gatenby, Beata Ujvari, Catherine Alix-Panabières and Frédéric Thomas

Cancers 2021, 13(15), 3693; https://doi.org/10.3390/cancers13153693 - 22 Jul 2021

Cited by 30 | Viewed by 4998

Abstract

The majority of cancer-related deaths are the result of metastases (i.e., dissemination and establishment of tumor cells at distant sites from the origin), which develop through a multi-step process classically termed the metastatic cascade. The respective contributions of each step to the metastatic process are well described but are also currently not completely understood. Is there, for example, a critical phase that disproportionately affects the probability of the development of metastases in individual patients? Here, we address this question using a modified Drake equation, initially formulated by the astrophysicist Frank Drake to estimate the probability of the emergence of intelligent civilizations in the Milky Way. Using simulations based on realistic parameter values obtained from the literature for breast cancer, we examine, under the linear progression hypothesis, the contribution of each component of the metastatic cascade. Simulations demonstrate that the most critical parameter governing the formation of clinical metastases is the survival duration of circulating tumor cells (CTCs). Full article

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Malignant and Non-malignant Atypical Circulating Cell in Cancer: Their Heterogeneity and Plasticity

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Published Papers (9 papers)

2023

Jump to: 2022, 2021

2022

Jump to: 2023, 2021

2021

Jump to: 2023, 2022

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